Estrogenic compounds and animal growth promoters



United States Patent O 3,373,026 ESTROGENIC COMPOUNDS AND ANHVIAL GROWTH PROMOTERS Edward B. Hodge, Phil H. Hidy, and Herbert L. Wehrmeister, Terre Haute, Ind., assignors to Commercial Solvents Corporation, a corporation of Maryland N Drawing. Continuation-impart of application Ser. No. 561,339, June 29, 1966. This application Mar. 3, 1967, Ser. No. 620,260

Claims. (Cl. 99-2) ABSTRACT OF THE DISCLOSURE This application is a continuation-in-part of application Ser. No. 561,339, filed June 29, 1966 now abandoned.

The present invention relates to new compounds and an object of the present invention is to provide compounds which exhibit estrogenic activity or aid in increasing the rate of growth in meat-producing animals, e.g., cattle,

lamb and swine.

The compounds of this invention are illustrated by the formula:

a o 0 cm some ' where A is CH -CH or CH=CH;

and R is hydrogen, substituted or unsubstituted alkyl,

e.g., lower alkyl such, as methyl, ethyl, hexyl, etc., or

aralkyl, e.g., benzyl.

The compounds of the present invention can be produced from the compounds:

OH 0 OH:

ICC

hereinafter referred to as the fermentation estrogenic substance (F.E.S.) by reaction with ethyl formate. The hydroxyl groups of PBS. are blocked against undesirable side reactions before reaction which can be accomplished by converting the hydroxyl groups to ethers, e.g., methyl ether-s, as taught in U.S. Patent 3,239,342, and subsequently removing the masking group to regenerate the hyd-roxyl group. The hydroxy group can be regenerated from, for example, a methyl ether by hydrolysis or by refluxing in acetic solution with hydrobromic acid. Aluminum chloride is another effective dealkylating agent. Benzyl groups are also effective masking groups and can be removed by reduction. Benzyl ethers of F.E.S. are described in copending application Ser. No. 532,113, filed Mar. 7, 1966, now abandoned and application Ser. No. 620,259, filed Mar. 3, 1967. Dihydro F.E.S. compounds where A is CH -CH are described in U.S. Patent 3,239,354. v

The compounds can be administered to animals by any suitable method including oral and parenteral administrations. For example, the compound can be blended with ordinary feed containing nutritional value in an amount sufficient to produce the desired rate of growth and can thus be fed directly to the animals, or the compound can be suspended in a suitable injection suspension medium such as peanut oil and injected parenterally. The amount of compound fed to an animal, of course, varies depending upon the animal, desired rate of growth and the like. When the new compounds are to be administered in feeds, an animal feed composition may be prepared containing the usual nutritionally-balanced quantities of carbohydrates, proteins, vitamins and minerals, together with the compound of the present invention. Some of these usual dietary elements are grains, such as ground grain and grain by-products; animal protein substances, such as those found in fish meal and meat scraps, vegetable proteins like soybean oil meal or peanut oil meal;

vitamin-aceous materials, e.g., vitamin A and D mixtures; riboflavin supplements and other vitamin B complex members; and bone meal and limestone to provide minerals. A type of conventional feed material .for use with cattle includes alfalfa hay and ground corn cobs together with supplementary vitaminaceous substances if desired.

The following examples serve to illustrate the invention.

Example I RES. 2,4-dimethylether (1.5 g.), ethyl formate (2 cc.) and finely divided sodium (1 g.) are allowed to react in benzene (30 cc.) for 15 hours at room temperature. The reaction mixture is then extracted with 200 cc. of Water. The water layer is acidified with hydrochloric acid liberate and warmed slightly to produce the compounds Example 11 Dihydro F.E.S. 2,4-diethyletlier and F.E.S 2,4 dibenzylether are reacted according to the procedure of Example I to produce the corresponding dihydro F.E.S. 2,4-diethylether and RES. 2,4-dibenzylether formyl derivatives.

Example III The products of Example I are dealkylated by heating at 120 C. in benzene with two equivalents of aluminum chloride to regenerate the hyd-roxyl groups.

Example IV Six head of cattle are fed a daily ration of alfalfa, hay and ground corn c-obs containing from 5 to 20 ounces per 100 pounds of feed of the compound of Example I and their rate of growth is improved.

Example V Six head of cattle are fed a daily ration of alfalfa, hay and ground corn cobs containing from 5 to 20 ounces per 100 pounds of feed of the compound of Example 11 and their rate of growth is improved.

The following are specific examples of animal feed compositions of this invention useful for increasing the rate of growth and feed efficiency of young animals to market weight.

Example V] For young beef cattle, i.e., calves to yearlings running to two year olds, each animal is given 5 to 20 milligrams per day of the compound produced in Example I intimately admixed in about 18 to 22 pounds per head per day of a complete pelleted ration for about 180 days. The complete pelleted ration includes in addition to the compound of Example Ithe following:

(Note: Milo or corn, for example, can be substituted for the barley.)

The compound of Example I is admixed with the above ingredients in a stationary blender or a feed mix truck in the following amounts in grams per ton to provide an appropriate complete pelleted feed with dosage levels ranging from 5 to 90 milligrams per head per day.

Grams/ton Mg./head/day .5 5 1.0 10 2.0 20 4.0 40 8 80 These gram amounts are premixed with, for example, 10 pounds of soybean hulls prior to admixture with the other ingredients.

Example VII For young swine, i.e., six week old pigs to about 100 pound pigs, each animal is given to 20 milligrams per day of the compound of Example III intimately admixed in about 1 /2 to 5 /2 pounds per head per day of a grower ration until it reaches a weight of about 100 pounds. When the swine weigh between 90 and 125 pounds the feed is changed to one whereby each animal is given 20 to 50 milligrams per day of the compound of Example III intimately admixed in about 5 /2 to 10 pounds per head per day of a finisher ration until it reaches market weight of about 220 pounds. The grower and finisher ration include in addition to the compound of Example III the following:

Grower, Finisher, percent percent Ground Yellow Corn 77 86. 7 Soybean Meal (44% protein) 16 6.5 Most and Bone Scraps (50% 2. 5 2. 5 Dohydrate Alfalfa Meal (17%) 2. 5 2. 5 Steamed Bone Meal 0.5 0.5 Ground Limestone 0. 5 0.3 Iodizcd Salt 0.5 0.5 Vitamin, Antibiotic and Trace N mix 0.5 0. 5

The compound of Example III is admixed with the above ingredients in a blender in the following amounts in milligrams per pound to provide an appropriate feed with dosage levels ranging from 6 to 96 milligrams per head per day.

Mg./pound Mg/head/day 2 6 4 12 8 24 16 48 32 96 Example VIII For 4 to 10 month old lambs weighing 50 to 70 pounds, each animal is given 1 to 15 milligrams per day of the compound of Example I, intimately admixed in about 3 to 6 pounds per head per day of a complete ration for 30 to days. The complete ration includes in addition to the compound of Example I the following:

Pounds Finely ground corn cobs 630 Ground corn 600 Dehydrated alfalfa meal 300 Dried molasses Soybean meal (44% protein) 300 Dicalcium phosphate 14 Trace mineral salt 17 Premix vitamin, mineral & antibiotic 19 The compound of Example I is admixed with the above ingredients in a blender in the following amounts in milligrams per pound to provide an appropriate complete feed with dosage levels ranging from 1 to 15 milligrams per head per day.

MgJpiound Mg./ head day 2 1.0 4 1.5 6 2.0 8

Example IX For broilers, i.e., day old to four week old chicks, a grower feed is prepared for feeding to the chicks for the first four weeks and a finisher feed is prepared for feeding the four week old chicks for the last five weeks until they reach market Weight of two and a half to three pounds dressed. For each pound of weight gain, the chicks eat about 1.5 to 2 pounds of feed. Thus they eat about 1.5 pounds of feed during the first four weeks and about five pounds of feed during the next five Weeks. During the course of this feeding schedule, each bird should receive a total of about 12 to 36 milligrams of the compound of Example III in the grower and finisher feed each of which includes in addition to the compound of Example III the following:

Grower Finisher (lbs) (lbs) 1,000 1, 200 700 500 100 80 50 50 O 30 r a l r l l 80 80 Dicalcium Phosphate 35 40 Iodized Salt 1O 10 10 Limestone 15 Premix Vita 15 R-O (I; (3H3 I OOCH(CH )z B 20 RO- 4 A 2):

where A is a radical selected from the group consisting of and and R is selected from the benzyl and lower alkyl.

2. The compound of claim 1 where R is lower alkyl. 3. The compound of claim 2 where A is H=CH-. 4. The compound of claim 3 where R is methyl. 5. The compound of claim 2 where A is group consisting of hydrogen,

No references cited.

A. LOUIS MONACELL, Primary Examiner.

H. H. KLARE, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,373,026 March 12, 1968 Edward B. Hodge et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 15 to 20, the right-hand portion of the formula should appear as shown below:

lines 45 to 50, the top portion of the formula should appear as shown below:

C-O-CH- CH 2 2 line 55, "B is" should be moved up to the left margin in larger print; lines 66 to 70, the right-hand portion of the formula reading should read Signed and sealed this 16th day of September 1969.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents 

